Mehdi El Amrani1,2, François Corfiotti1,2, Matthieu Corvaisier2, Romain Vasseur2, Maxence Fulbert1,2, Cécile Skrzypczyk1,2, Anne‐Claire Deshorgues1,2, Viviane Gnemmi2,3, David Tulasne4, Fatima Lahdaoui2, Audrey Vincent2, François‐René Pruvot1,2, Isabelle Van Seuningen2, Guillemette Huet2, Stéphanie Truant1,2
1Department of Digestive Surgery and Transplantation, CHU Lille, Lille, France
2Department of Digestive Surgery and Transplantation Université de Lille, Inserm, CHU Lille, UMR‐S 1172 Lille France
3Department of Pathology, Center of Biology‐Pathology CHU Lille Lille France
4Institut Pasteur de Lille, UMR 8161‐M3T, Mechanisms of Tumorigenesis and Target Therapies Université de Lille, CNRS Lille France
Tóm tắt
AbstractGrowing body of evidence suggests that epithelial‐mesenchymal transition (EMT) is a critical process in tumor progression and chemoresistance in pancreatic cancer (PC). The aim of this study was to analyze the role of EMT‐like changes in acquisition of resistance to gemcitabine in pancreatic cells of the mesenchymal or epithelial phenotype. Therefore, chemoresistant BxPC‐3, Capan‐2, Panc‐1, and MiaPaca‐2 cells were selected by chronic exposure to increasing concentrations of gemcitabine. We show that gemcitabine‐resistant Panc‐1 and MiaPaca‐2 cells of mesenchymal‐like phenotype undergo further EMT‐like molecular changes mediated by ERK‐ZEB‐1 pathway, and that inhibition of ERK1/2 phosphorylation or ZEB‐1 expression resulted in a decrease in chemoresistance. Conversely, gemcitabine‐resistant BxPC‐3 and Capan‐2 cells of epithelial‐like phenotype did not show such typical EMT‐like molecular changes although the expression of the tight junction marker occludin could be found decreased. In pancreatic cancer patients, high ZEB‐1 expression was associated with tumor invasion and tumor budding. In addition, tumor budding was essentially observed in patients treated with neoadjuvant chemotherapy. These findings support the notion that gemcitabine treatment induces EMT‐like changes that sustain invasion and chemoresistance in PC cells.
